This Center for Medications Development (MDU) has a theme of developing new GABA enhancing medications and using genetic approaches to optimally match successful cocaine pharmacotherapies such as disulfiram and the GABA reuptake blocker tiagabine to subgroups of cocaine dependent patients- We are conducting two outpatient randomized clinical trials and a series of five laboratory screening studies for new GABA enhancers. The first project is a randomized, placebo-controlled, 12-week clinical trial examining 150 cocaine-dependent methadone-stabilized patients in a trial of disulfiram and the GABA reuptake blocker tiagabine. These patients will be stratified based on a functional dopamine beta hydroxylase (DBH) polymorphism with the prediction of a treatment response to disulfiram only in those with the genetic haplotype that leads to low OBH levels and relatively higher dopamine (DA) levels. The second project includes 140 depressed. recently abstinent, cocaine-dependent patients in a randomized, placebo-controlled, 12-week relapse trial with four treatment groups: placebo, sertraline. sertraline + tiagabine and sertraline + gabapentin. This trial includes an initial 2 weeks of inpatient abstinence. The patients in both projects will undergo genetic screening of GABA related polymorphisms as potential predictors of treatment response to GABA enhancers in future studies. The third project will use cocaine administration to humans in a laboratory in order to screen five GABA enhancers for their potential utility as pharmacotherapies. These three projects involve examination of nine different potential cocaine pharmacotherapies in clinical trials and the human laboratory. These clinical trials offer an interesting contrast in DA enhancement by disulfiram or the DA reuptake blocker sertraline versus DA reduction by the GABA enhancers - tiagabine and gabapentin. Overall, over 300 patients will be studied in this Center and eight different agents in either outpatient Phase II trials or human laboratory studies.